It is well known that plasma vasopressin concentrations are elevated following emesis. It has been reported that arginine vasopressin (AVP) is a mediator of chemotherapy-induced emesis. In motion sickness studies, a sharp rise in AVP has been reported and it has been suggested that stimulation of AVP release may be the first and most significant response to stressful motion stimuli. In motion sickness studies recently conducted on astronauts, it was observed that the astronauts experiencing motion sickness exhibited high circulating plasma vasopressin concentrations. Thus, an emetic stimulus may stimulate vasopressinergic pathways in the brain which may stimulate the emetic center and thus result in emesis.
The pressor and antidiuretic activities of vasopressin are mediated by separate receptor pathways identified as V.sub.1 and V.sub.2, respectively. A number of synthetic modifications of the vasopressin structures have been reported to give antagonistic activities. U.S. Pat. No. 4,399,125 discloses vasopressin antagonists of the antidiuretic activity of arginine vasopressin. These peptide structures are characterized in that the 1 position has a 1-.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic-acid group (Pmp). Basic v.sub.1 - vasopressin antagonists are disclosed in U.S. Pat. No. 4,604,378 characterized in that the peptides have an acyclic unit at position 1, i.e., a 1-desamino-penicillamine group. None of the known art discloses the biological activities of the claimed compositions and methods of this invention.
In the description herein and in the claims, the nomenclatue common in the art of peptide and more specifically, vasopressin chemistry is used. When no configuration is noted, the amino acid unit is in the L, or naturally occurring, form. The thio members of the .beta.-mercapto-propionic acid (1) and cysteine (6) units are added for clarity in certain structural formulas.
Exemplary of the peptide abbreviations used herein are the following: Gly, glycine; Tyr, tyrosine; Phe, phenylalamine; Arg, arginine; Ile, isoleucine; Asn, asparagine; Val, valine; Gln, glutamine; Pro, proline; Leu, leucine; Lys, lysine; Cys, cysteine; Mpr, .beta.-mercaptopropionic acid; d Pen, .beta.-mercapto-.beta.-.beta.-dimethylpropionic acid; Ala, alanine.
It is an object of this invention to provide antagonists of vasopressin-mediated emetic responses. It is a further object to provide a method for preventing nausea and emesis due to motion sickness and other etiologies.
Examples of V.sub.1 antagonists that may be employed in this invention are the des-Pro-vasopressin-like compounds set forth in U.S. Pat. No. 4,599,324, preferably [1-deaminopenicillamine-2-D-(o-ethyl)tyrosine-7-desproline-8-arginine 9-desglycine] vasopressin. Further examples of V.sub.1 -vasopressin antagonists useful in this invention are set forth in U.S. Pat. No. 4,604,378, U.S. Pat. No. 4,684,622, U.S. Pat. No. 4,658,015, and U.S. Pat. No. 4,684,624.